Learned associations between drug effects and the people, places and paraphernalia (cues) surrounding drug experiences represent a major barrier to the successful treatment of drug addiction; these associations are remarkably persistent, despite efforts to extinguish them, and can trigger drug craving and relapse even after long periods of abstinence. Thus, associations between drugs and drug cues constitute a unique target for treatment but there is little clinical evidence of how the associations are formed, and limited empirical support for a direct effect of cues on drug consumption. The long-term goal of this research is to understand how drug cues become powerfully linked with drug experiences, their influences on physiology and behavior, and how they promote drug consumption and addiction. The objective of the proposed research project is to determine how associations between d-amphetamine and the places where it is experienced influence mood, behavior and acute responses to the drug in recreational drug users. The applicants have developed a novel model, which is particularly well-suited to studying conditioned drug associations because exposure to d-amphetamine and the drug-paired environment can be carefully controlled allowing a comprehensive analysis of the results. The working hypothesis is that d-amphetamine conditioned cues (contexts) alter behavior and subjective responses to the drug which influences the overall rewarding efficacy of the drug. The rationale for the project is that vital knowledge regarding conditioned responses to drug-paired contexts will lead to novel strategies to counteract responses to conditioned drug cues, their influence on behavior, and drug consumption. The hypothesis, based upon strong preliminary data from the applicants' laboratory, will be tested by three specific aims: 1) Establish a conditioned association between d- amphetamine and a distinct environment that induces approach to that environment i.e., drug-seeking behavior, 2) Determine how individual differences in acute subjective responses to d-amphetamine influence the development of conditioned associations between the drug and environments, and 3) Identify conditioned mood and subjective responses to d-amphetamine in the drug-paired context. We believe that the proposed plan of research is innovative because it will examine how conditioned associations between d-amphetamine and contexts are formed in humans and the influence of the conditioned associations on behavior, mood and acute subjective responses to the drug. This research project is significant because it will substantiall advance and expand our understanding of how conditioned associations between drugs and cues are acquired in humans with limited drug experiences, and of their influence on drug seeking and drug reward. Ultimately this knowledge is expected to inform the development of novel strategies and pharmacotherapies to counteract responses to the conditioned cues in effective treatment approaches.